PB1770: CHARACTERIZATION OF THE MUTATIONAL PROFILE OF PATIENTS WITH CBF-AML - HETEROGENEITY AND IMPACT ON THE PROGNOSIS
Authors: Ekaterina Motyko, Anna Kirienko, Daria Kustova, Asiyat Rajabova, Olga Uspenskaya, Elena Karyagina, Vasiliy Shuvaev, Sergey Voloshin, Sergey Sidorkevich, Irina Martynkevich
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16) and t(8;21). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. Aims: To analyze the genomic heterogeneity of CBF-AML using NGS and assess the impact of the most frequent aberrations on prognosis. Methods: The study included 46 CBF-AML pts - 22 pts with inv(16) and 24 pts with t(8;21). Samples were analyzed by high-throughput sequencing on MiSeq platform (Illumina, USA). A panel consisting of 118 genes was developed based on literature data. Results: 97 mutations were found in 48 of 118 target genes: 60 mutations in AML pts with t(8;21) and 37 mutations in those with inv(16). In 21 genes, mutations were detected repeatedly (≥2 times). At least 1 mutation was detected in 95.8% of pts with t(8;21) and 95.5% of pts with inv(16). On average, significantly more mutations were found in AML pts with t(8;21) than in AML pts with inv(16), 2.6 versus 1.9 mutations, respectively (p=0.04). In AML pts with t(8;21), 41 different genes were mutated; with inv(16), 19 genes contained mutations. Of the 48 affected genes, mutations in 12 genes were common in both CBF-AML subgroups, whereas pts with t(8;21) had a higher proportion of private mutations (70.7% (29) versus 36.8% (7), respectively). Mutations in RTK/RAS signaling pathways were the most common events in the two types of CBF-AML, with the highest incidence in NRAS+KRAS (26.1%; t(8;21), 12.5%; inv(16), 40.9%), KIT (19.6%; t(8;21), 20.8%; inv(16), 18.2%) and FLT3 (4.3%; t(8;21), 0%; inv(16), 9.1%). Characterization of the molecular genetic profile of pts with t(8;21) AML: mutations in epigenetic regulation genes ASXL1 (16.7%) and EZH2 (4.2%), DNA methylation - DNMT3A (4.2%), cohesion complex - RAD21 (8.3%) and SMC3 (8.3%), MGA (16.7%), involved in MYC signaling pathway, SH2B3 (8.3%), SETBP1 (8.3%) that were absent in AML with inv(16) were found. Molecular genetic profile of pts with inv(16) AML: aberrations of genes involved in chromatin modification were rare events (in the ASXL1 gene - 0%), as were mutations related to the cohesion complex, which were absent in all cases. A mutation in the transcriptional corepressor BCORL1 was detected in one pnt. Approximately half (45.7%) of pts with CBF-AML had mutations in genes that activate signaling pathways, and the prognostic significance of such mutations was examined (Fig.1). A significant increase in the risk of relapse was found in pts with these mutations compared to pts without them (p=0.046). Pts with mutations in KIT gene had a significantly worse recurrence-free survival rate than pts without the mutation (p=0.031).Fig. 1. RFS of CBF-AML pts with and without mutations in genes that activate signaling pathways Summary/Conclusion: Patients with CBF-AML have a highly heterogeneous molecular genetic profile. Two CBF-AML groups hold their own unique genetic features, what makes it appropriate to analyze them separately in the research. The most frequent molecular events in CBF-AML are mutations in N/KRAS, KIT and FLT3 genes, which activate intracellular signaling pathways involving tyrosine kinases. Mutations in KIT gene and other mutations in genes involved in the activation of signaling pathways negatively affect the relapse-free survival of pts with CBF-AML. The use of the latest molecular genetic technologies, such as NGS, makes it possible to obtain a detailed characterization of the mutational profile for each pt, which is critical for CBF-AML pts, given the high frequency of mutations in them and the development of effective targeted therapy. Keywords: Core binding factor leukemia, Prognosis, Mutation analysis